(+)-Asocainol or (+)-2,12-dimethoxy-1-hydroxy-7-methyl-6-phenethyl-5,6,8,9-tetrahydro-7H-di benz(d,f)azonine or R,R-asocainol is a pharmaceutically active compound described in German Pat. No. 30 07 710. The compound is especially useful as a local anaesthetic and an antiarrhythmic.
In the case of the synthesis of (+)-asocainol according to German Pat. No. 30 07 710, from natural thebaine (see Merck Index, 10th edition, 1983, No. 9097), the hydrochloride is obtained in a yield of 21% of theory. Besides the desired (+)-asocainol with the R,R-configuration, there is formed, in the extremely unfavorable weight ratio of 1:3.25, the ineffective and therefore useless diastereomer with the R,S-configuration. All attempts to shift this unfavorable isomer ratio by alteration of the synthesis parameters, for example by the use of different solvents and variation of the temperature, amount ratio or of the concentration in favor of an increase in yield of the desired isomer remained unsuccessful.
In German Pat. No. 34 19 099, (-)-asocainol (the S,S-isomer) is described as obtainable from the ineffective R,S-isomer by thermal isomerization; it also displays an antiarrhythmic effect. In the case of the synthetic formation of the racemate (R,R; S,S) of equal parts of asocainol in the R,R- and S,S-form, there was a surprising pharmacological finding; instead of the expected additive action, there was a stronger synergistic antiarrhythmic effect by means of which there was considerably improved effectiveness in comparison with (+)-asocainol.
In the case of the thermal rearrangement described in the German Pat. No. 34 19 099 at temperatures of from 130.degree. to 200.degree. C. in the melt or in high boiling point solvents, there is formed, in equilibrium with the starting material, in about 40% yield, the S,S-enantiomer which can be separated by fractional crystallization, for example, as the hydrochloride. By recycling the unreacted R,S-isomer, practically all of the R,S-isomer can be converted into the S,S-form and thus, besides about 17 to 20% of (+)-asocainol (R,R), there can also be obtained about 45 to 50% (-)-asocainol (S,S).
Since, however,as stated above, the greatest action is not obtained with the isomers but with the racemate, this means an undesired excess of S,S-isomer.
Therefore, the problem is to find a process for the isomerization of asocainol whereby the (+)-asocainol (R,R) can also be obtained in order to be able to prepare the highest possible yields of the racemic (.+-.)-asocainol.
According to the X-ray structural analysis, (+)-asocainol possesses an absolute configuration according to the following formula: ##STR1##
Theoretically, as described in German Pat. No. 34 19 099, asocainol can occur in four different forms which are due to
1. the asymmetric carbon atom in the 6-position and PA1 2. the biphenyl asymmetry at the 13a-13b bond. PA1 1. racemization of the R,S-compound to the diastereomeric (S,R; R,S) racemate and subsequent thermal rearrangement of this racemate into racemic asocainol according to German Pat. No. 34 19 099; PA1 2. inversion of the R,S-compound to the S,R-compound and thermal rearrangement of this compound to (+)-asocainol according to German Pat. No. 34 19 099; PA1 3. change of the configuration on the optically-active C6 atom of the R,S-compound from the S- to the R-configuration, (+)-asocainol thereby being formed; PA1 4. simultaneous change of the configuration on the optically-active C6 atom of the R,S-compound from the S- to the R-configuration, (+)-asocainol thereby being formed, and rearrangement of the biphenyl system of the R,S-compound from the R- to the S-configuration to give (-)-asocainol, with the direct formation of the racemic asocainol; both reactions must proceed with the same velocity. PA1 (a) dissolving asocainol isomers in an organic or organic acid, optionally with a polar solvent, PA1 (b) adding a catalytic amount of a salt and an oxidation agent and/or a salt with an oxidising activity to, the solution PA1 (c) heating the above solution to between 60.degree. and 118.degree. C. to give partial isomerization.
The biphenyl asymmetry is brought about because the two phenyl rings do not lie in one plane but rather are arranged almost vertically to one another. Consequently, the following configurations are conceivable: (R,R), (S,S), (R,S), and (S,R). The pair (R,R) and (S,S), as well as the pair (R,S) and (S,R), are enantiomers which theoretically can each form a racemate. Since, in their structure, enantiomers behave like image and mirror image, they are the same in all physical properties apart from the sign of the rotation of polarized light.
Because of the presence of two chiral centers, in the case of asocainol, besides the optical isomerism, there also occurs diastereomerism. Diastereomers are characterized by the fact that they do not have an image-mirror image relationship to one another.
Thus, the pair (R,R) and (S,S) is diastereomeric to the pair (S,R) and (R,S). In the same way, the racemate (R,R-S,S) is a diastereomer of the racemate (S,R-R,S). The configuration first mentioned in the case of the pairs refers, in each case, to the biphenyl asymmetry and the second to the asymmetric carbon atom in the 6-position. (S,R) means S-configuration with regard to the biphenyl asymmetry and R-configuration on C6.
In Scheme II below there are the four possible configurations and their racemates. In addition, in each case the optical rotation is shown. ##STR2##
Starting from the R,S-isomers obtained in excess in comparison with the R,R-isomers or from the S,S-isomers obtainable therefrom, various ways were theoretically conceivable for an isomerization for obtaining additional R,R-isomers or the desired racemate:
The essential step in the case of all four routes is the change in the configuration of the optically-active C6 atom which, apart from carbon and hydrogen, carries a tertiary amine as the fourth substituent.
Routes 1 and 2 cannot be used because R,S-asocainol could not be racemized with the formation of S,R-asocainol nor could it be isomerized.